A, In the normal gut, easily digestible starch undergoes complete
digestion and absorption within the proximal small intestine and is not available
for fermentation in the distal ileum and colon where bacterial colonization
is the greatest.29- 31 In
contrast, gas production results from bacterial fermentation of poorly digestible
starch that is not assimilated by the proximal gut. B, In small intestinal
bacterial overgrowth, the concentration of bacterial flora increases proximally
allowing fermentation of both easily digestible and poorly digestible starches.

Detection of SIBO depends on location of and access to bacterial
flora. SIBO by culture is defined by bacterial concentration proximal to the
distal ileum >105 organisms per mL. In this example of SIBO, the
concentration of bacterial flora in the distal jejunum and ileum has increased
to that typically present in the normal colon (1011 organisms per
mL). Culture of intestinal flora sampled by direct aspiration, which commonly
is able to access the duodenum, would not detect the region of increased bacterial
flora in this example. Similarly, a breath test using glucose as the fermentable
substrate would only detect bacterial flora in the duodenum and proximal jejunum
because glucose is rapidly absorbed. In contrast, a breath test using lactulose,
which is not absorbed by the intestine, would be able to detect bacterial
flora anywhere along the gut.

Bulbring E, Lin RC. The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan
on peristalsis: the local production of 5-HT and its release in relation to
intraluminal pressure and propulsive activity. J Physiol (Lond).1958;140:381-407.PubMedGoogle Scholar

Context Irritable bowel syndrome (IBS), which affects 11% to 14% of the population,
is a puzzling condition with multiple models of pathophysiology including
altered motility, visceral hypersensitivity, abnormal brain-gut interaction,
autonomic dysfunction, and immune activation. Although no conceptual framework
accounts for all the symptoms and observations in IBS, a unifying explanation
may exist since 92% of these patients share the symptom of bloating regardless
of their predominant complaint.

Evidence Acquisition Ovid MEDLINE was searched through May 2004 for relevant English-language
articles beginning with those related to bloating, gas, and IBS. Bibliographies
of pertinent articles and books were also scanned for additional suitable
citations.

Evidence Synthesis The possibility that small intestinal bacterial overgrowth (SIBO) may
explain bloating in IBS is supported by greater total hydrogen excretion after
lactulose ingestion, a correlation between the pattern of bowel movement and
the type of excreted gas, a prevalence of abnormal lactulose breath test in
84% of IBS patients, and a 75% improvement of IBS symptoms after eradication
of SIBO. Altered gastrointestinal motility and sensation, changed activity
of the central nervous system, and increased sympathetic drive and immune
activation may be understood as consequences of the host response to SIBO.

Irritable bowel syndrome (IBS) is a common diagnosis that affects 11%
to 14% of the population.1,2 Currently,
IBS is a diagnosis made on the basis of meeting clinical criteria.3- 6 This
symptom-based approach has been used because no consistent biological marker
or unifying framework has been available to explain the different symptoms
and findings of IBS. The varying symptoms in IBS have led to efforts looking
at differences rather than similarities between patients.6

Another way we have emphasized the difference rather than the similarity
is in the grouping of one set of symptoms of these patients as IBS and another
set of symptoms as belonging to some other diagnosis. The clinical criteria
for IBS do not include the extraintestinal symptoms that are common in these
patients such as fatigue or myalgia. Instead, these complaints are viewed
as symptoms of other diagnoses that coexist with IBS such as chronic fatigue
syndrome7 and fibromyalgia.8 This
separation may be an artifact of medical specialization.9 As
such, a unifying framework for understanding IBS that could account for both
the gastrointestinal as well as the extraintestinal symptoms of these patients
would warrant serious consideration.

Evidence acquisition

Ovid MEDLINE was searched through May 2004 for articles using combinations
of the terms bloating, gas, IBS, post-infectious IBS, small intestinal bacterial overgrowth (SIBO), microbial translocation, bacteria, visceral hypersensitivity, immune response, autonomic dysfunction, central nervous
system, intestinal motility, fibromyalgia, chronic fatigue syndrome, interstitial cystitis, lactulose and
glucose breath test, and sickness behavior.
Additional sources were identified by scanning through the bibliographies
of articles and books. Publications reviewed ranged from randomized controlled
trials to case-control studies. Although randomized controlled trials were
considered to be the strongest evidence, such studies were few, so the evidence
was considered to be most compelling when there was consistency among the
results of multiple different studies. Quality of data was assessed by publication
in a peer-reviewed journal. A few critical recent abstracts were also considered.

Evidence synthesis

Postprandial Bloating as a Unifying Symptom of IBS

Quiz Ref IDRegardless of whether an IBS patient is troubled predominantly
by constipation, diarrhea, or pain, 92% of IBS patients complain of bloating
and pain, with 89% having a bloating score of 5 or greater (out of 10).10 Although many IBS patients describe worsening of
their symptoms by food intake,11 most are unsuccessful
in identifying a food trigger.12 This extremely
common complaint of postprandial bloating4 supports
the possibility of a unifying pathophysiology. This symptom is associated
with abdominal distension and has been corroborated by direct physical evidence
of increased intestinal gas as measured by abdominal films,10,13 computed
tomography of the abdomen,14 and plethysmographic
measurement showing increased abdominal girth at the end of the day but decreased
girth overnight after fasting.15,16 The
possibility of a unifying explanation for IBS is further supported by reproducible
x-ray findings of Koide et al13 in which increased
intestinal gas was noted regardless of bowel movement pattern. Of note, the
increased gas was localized to the small rather than the large intestine.

Intestinal Gas Excretion Is Greater in IBS

Although in some studies intestinal gas volume of IBS patients has been
reported to be no different than that of healthy controls,17,18 the
gas measurement in these studies was done in a fasting state. As such, no
conclusion can be drawn from these studies regarding meal-induced bloating
in IBS patients. In contrast, both total hydrogen production (median, 332
vs 162 mL) and maximal rate of gas excretion (2.4 mL/min vs 0.6 mL/min) were
greater following lactulose ingestion in IBS patients (6 subjects) than healthy
controls.19 This finding of a 4-fold greater
rate of maximal gas excretion and greater total hydrogen excretion provided
direct evidence of increased gas production in IBS in the presence of a fermentable
substrate. Since the excreted gases were hydrogen and methane, this abnormal
response to lactulose in IBS patients cannot be explained by a disaccharide
intolerance.20 This group reported similar
findings in another study where the 24-hour total excretion of hydrogen following
lactulose was substantially greater in IBS patients (median, 333.7 mL/24 h;
interquartile range, 234.7-445.67 mL) than in normal volunteers (median, 203.1
mL/24 h; interquartile range, 131.4-256 mL; P = .002)
or IBS patients who failed exclusion diet (median, 204 mL/24 h; interquartile
range, 111.35-289.13 mL; P = .02).21 Current
construct models of the pathophysiology of IBS, including abnormal motility,22 visceral hypersensitivity,23 altered
brain-gut interaction,24 autonomic dysfunction,25 and immune activation,26 do
not account for the nearly universal symptom of postprandial bloating, the
physical evidence of increased intestinal gas that is localized to the small
intestine, the effect of probiotics on bloating,27 or
the increased gas excretion after lactulose ingestion.19,21

Normal Intestinal Gas Production

From the seminal work of Levitt,28 we
know that the site of hydrogen production by bacterial fermentation is limited
to the distal gut. The duodenum and jejunum are often sterile, and the proximal
ileum may be sterile. The concentration of gut bacteria drops precipitously
from 1010-12 organisms per mL in the cecum to 105-8 organisms
per mL in the terminal ileum, 100-5 in the proximal ileum, and
100-4 in the jejunum and the duodenum.29- 31 For
fermentation to begin, food must reach these distal gut bacteria. In the normal
state, the digestibility of dietary starch is the primary determinant of how
much bacterial fermentation takes place in the gut (Figure 1).32 The elimination of the
hydrogen produced by bacterial fermentation depends significantly on methanogenic
and sulfate-reducing bacteria that convert hydrogen to methane and hydrogen
sulfide.33 These organisms are highly competitive
so that the stool of an individual contains high concentrations of only 1
of these 2 types of organisms.

If Not the Food, the Problem May Be the Bacteria

Since no specific food intolerance can explain the greater increase
in hydrogen excretion after lactulose ingestion,19 the
abnormal fermentation problem may not be the food but rather, the gut bacteria.
If food is not moving down to the bacteria, then bacteria may be moving to
the site of food assimilation for fermentation and gas production to take
place. SIBO describes just such proximal expansion of gut bacteria (Figure 1) and provides a biologically plausible
framework for the bloating of IBS. What evidence is there to support the role
of bacterial overgrowth in IBS?

Prevalence of SIBO and Effect of Antibiotic Treatment in IBS

In a study of 202 patients meeting Rome I criteria for IBS by Pimentel
et al,34 an abnormal breath test result suggesting
SIBO was found in 78%. In this uncontrolled study, when the second breath
test result after antibiotic treatment became normal, consistent with successful
eradication of bacterial overgrowth, symptoms were reduced enough so that
only half of the patients still met clinical criteria for IBS. The possibility
of bacterial overgrowth as a unifying framework for understanding the symptoms
of IBS patients is further supported by reduction of both gastrointestinal
and extraintestinal symptoms when eradication of SIBO was achieved.34 However, it is not clear at this time whether alteration
of colonic bacterial flora by antibiotics may also play a role in symptom
improvement.

Quiz Ref IDThese findings were then corroborated by a double-blind,
randomized, placebo-controlled study by Pimentel et al35 where
111 patients were drawn from the general IBS population, with no a priori
selection on the basis of chief complaint. The prevalence of abnormal lactulose
breath test result in this controlled study was 84% vs 20% in the control
subjects who did not meet Rome I criteria (odds ratio, 26.2; 95% confidence
interval, 4.7-103; P<.001). There was a graded
effect of treatment whereby the mean (SE) normalization of global symptoms
within 1 week of randomization was 11.0% (3.7%) for placebo-treated patients,
36.7% (6.1%) for antibiotic-treated patients who did not achieve bacterial
eradication, and 75.0% (6.4%) for antibiotic-treated patients who also achieved
bacterial eradication (P<.001, 1-way analysis
of variance). This graded response is consistent with an antibiotic-sensitive
pathophysiology of IBS. A similar study consistency was demonstrated by a
double-blind, placebo-controlled study that showed metronidazole to be superior
to placebo in relieving symptoms in IBS patients,36 while
another recent report by Nucera et al37 showed
that 75% of 200 IBS patients have an abnormal lactulose-glucose breath test
result consistent with the presence of SIBO.

The Type of Gas May Contribute to Constipation

If SIBO provides a unifying framework for understanding IBS patients,
how does this account for the possibility of both constipation and diarrhea?
The type of gas produced by gut bacteria may be an important factor. In 2
studies by Pimentel et al,35,38 excretion
of methane alone was only found in constipation-predominant IBS patients.
Methane as a gas slows intestinal transit39 and
reduces postprandial plasma level of serotonin,40 the
mediator of the peristaltic reflex.41 Methane
excretion has been found in 65% of children with encopresis compared with
15% of the control patients.42 A role for gut
bacteria as one of the factors in constipation is further suggested by the
observation in 8 patients with chronic idiopathic constipation that stool
frequency and consistency improved after a 14-day course of antibiotics.43

Abnormal Small Intestinal Motility May Explain SIBO in IBS

Quiz Ref IDBetween meals, the interdigestive motility of the upper
gastrointestinal tract is characterized by a cyclical pattern of activity
known as the major migrating complex (MMC).44 The
MMC includes a period of powerful, lumen-obliterating contractions that propagates
from the stomach or duodenum distally to the terminal ileum (phase III of
MMC or the intestinal housekeeper wave).44 When
compared with recordings from healthy controls, the frequency of these intestinal
housekeeper waves was significantly reduced in IBS patients,45 which
may also explain the abnormal gas retention that is observed in IBS patients.18 The importance of the relationship
between abnormal phase III of MMC and SIBO was first described by Vantrappen
et al46 in patients with organic gastrointestinal
disorders and extended in animal and human studies to the relationship between
small bowel motility and gut bacteria47,48;
small bowel motility and SIBO49; and small
bowel motility, SIBO, and bacterial translocation.50

Why Is Prevention of SIBO Important?

Quiz Ref IDBacterial translocation, a known complication of SIBO,51 is the movement of gut bacteria from the lumen across
the mucosal barrier.52 In rats, experimentally
induced SIBO leads to the appearance of gut bacteria in the mesenteric lymph
nodes and visceral organs.49 A potentially
important consequence of bacterial translocation is immune activation. In
a report of 11 patients, an increase in the number of intraepithelial lymphocytes
was observed as mucosal evidence of this immune response to confirmed bacterial
translocation.53 This adverse outcome
could explain why the normal gut has defensive mechanisms in place to keep
the bacterial flora away from the small intestine, particularly the bowel
proximal to the ileum.

Immune Activation Is Also Present in IBS

Mucosal evidence of an activated immune response has been reported recently
in patients who develop IBS after recovering from acute gastroenteritis (postinfectious
IBS)54- 56 and
in those without such history.57,58 Of
the IBS population, 25% to 30% of patients have an antecedent history of acute
gastroenteritis.54,55,59 In
these reports, postinfectious IBS patients have an increased number of intraepithelial
lymphocytes,59,60 just like the
patient with documented bacterial translocation.53

An episode of acute gastroenteritis is not needed to explain immune
activation in IBS. In a study of 77 IBS patients, an increase in the number
of activated intraepithelial lymphocytes was found in almost 90% of the subjects
regardless of the acuteness of their onset or their predominant gastrointestinal
symptom.26 The magnitude of the immune activation
in patients without a history of acute gastroenteritis is, in fact, even more
prominent than those with that history.26 These
observations have provided strong study consistency in support of the biological
plausibility for a role of inflammation in IBS as proposed by Collins.61- 63 Any framework for
understanding IBS must, therefore, account for these and other observations
of immune activation.26,54,57,59 The
role of an underlying process that involves inflammation in IBS is further
supported by observations of a genetic predisposition in some IBS patients
to produce less anti-inflammatory products64 or
more pro-inflammatory products.65 Although
the trigger for the immune response in IBS has not been identified, SIBO would
provide a framework for understanding the activated immune response in IBS.
In postinfectious IBS patients, along with immune activation, there is also
increased intestinal permeability,59,66 which
has a known association with SIBO in animals67 and
humans68 as the experimental correlate of the
"leaky gut syndrome."

Quiz Ref IDLipopolysaccharide, an endotoxin of gram-negative bacteria,
accelerates intestinal transit.69 This may
be mediated by mast cell degranulation, immune activation, cytokine production,
and the triggering of preprogrammed responses of the enteric nervous system,
including hypersecretion and power peristalsis70 leading
to diarrhea and cramping abdominal pain. Visceral hypersensitivity
has been reported as a characteristic of IBS.23 The
immune response to these bacterial products would also explain this finding.
Lipopolysaccharide has also been reported to induce visceral hypersensitivity
in rats.71 Weston et al72 proposed
earlier that increased mast cells in the ileum of IBS patients might be linked
to altered visceral perception.

Similar to IBS, Fibromyalgia May Also Be Explained by SIBO

It is well recognized that there is a high degree of overlap between
IBS, fibromyalgia, interstitial cystitis, and chronic fatigue syndrome.7,73,74 While interstitial
cystitis75 and IBS23 are
diagnoses associated with hypersensitivity at the level of the bladder and
gut, respectively, fibromyalgia may be considered a kind of hypersensitivity
at the musculoskeletal level.73 Although the
cause of the hypersensitivity in these disorders is not well understood, the
striking overlap of hypersensitivity in these functional disorders suggests
the possibility of a unifying explanation. In a study of patients meeting
American College of Rheumatology criteria for fibromyalgia, an abnormal lactulose
breath test result suggesting SIBO was found in 42 out of 42 patients.38 Fibromyalgia patients had a higher breath hydrogen
concentration than IBS patients. Thus, an abnormal breath test result suggesting
SIBO may reflect a common pathophysiological link between fibromyalgia and
IBS. The immune response to bacterial antigen in SIBO provides a framework
for understanding the hypersensitivity in both fibromyalgia and IBS.

Controversies

Diagnostic Approach to SIBO

Since direct culture is usually considered the gold standard for the
diagnosis of a bacterial disease, the use of an indirect approach such as
the lactulose breath test for the diagnosis of SIBO is controversial. When
it comes to diagnosing SIBO, the problem with the direct approach is one of
access. While bacterial overgrowth can occur only in the more distal portions
of the 300- to 500-cm length of the small intestine,76 direct
aspiration and culture are limited by the reach of instrumentation. Since
only the small intestine proximal to the ligament of Treitz is usually reached
by an endoscope (∼60 cm), there is a high false-negative rate with this
approach for the diagnosis of SIBO.77,78 Even
with these limitations of access, Simren et al79 reported
that 4 (12%) of 33 IBS patients had more than 100 000 colony-forming
units of bacteria of colonic origin in the duodenum. While the prevalence
is considerably lower than that detected by lactulose breath testing,34,35,37 this study provided
direct confirmation of the expansion of colonic bacteria proximally all the
way to the duodenum in some IBS patients. Using glucose instead of lactulose
as the substrate for a breath test is similarly limited,80 since
glucose is rapidly absorbed with the fermentable substrate removed from the
lumen of the upper small intestine. In contrast, since lactulose is poorly
digestible, this fermentable substrate does remain available in the lumen
for fermentation by gut bacteria anywhere along the gut (Figure 2).

Interpreting a Premature Rise of Breath Hydrogen

A premature rise of breath hydrogen is a feature of both bacterial overgrowth
and excessively rapid transit. However, 2 observations point away from rapid
transit as the primary explanation for the findings by Pimentel et al.34,35 First, the time-to-rise of breath
hydrogen normalized with successful eradication of SIBO by antibiotics in
the IBS patients.35 Second, the abnormal gas
profiles of the constipation-predominant IBS (slow transit) patient overlapped
with that of the diarrhea-predominant IBS patients (fast transit).

Role of Sugar Intolerance in IBS

There has been recent interest in fructose intolerance as a possible
explanation for unexplained gastrointestinal symptoms.20 Interestingly,
there is a similar pattern of malabsorption in IBS patients across a number
of tested fermentable substrates.81 For many
patients, the association between sugar intolerance and IBS may be related
to bacterial overgrowth rather than true sugar intolerance. Nucera et al37 found a high rate of disappearance of malabsorption
to lactose (86.6%), fructose (97.5%), and sorbitol (90.9%) once SIBO was eradicated.
Similarly, Pimentel et al reported that while the number of IBS patients with
true lactose intolerance was low (16%), a much higher number (58%) had an
abnormal lactose breath test result and there was a significant correlation
between lactulose (SIBO) and lactose breath test result.38

Abnormalities of autonomic nervous system function, including disturbed
sleep,82 have been described in patients with
IBS.25 Using SIBO as a framework for understanding
IBS, these neural changes can be understood on the basis of 2-way triggered
communications between the immune system and the autonomic nervous system.83 An example of this interaction is the defensive sympathetic
response to stress involving immune activation of noradrenergic neurons.84 Using a variety of brain imaging techniques, IBS
patients have been observed to exhibit a different pattern of brain response
to visceral stimuli than healthy control subjects.24 Since
inflammation in animal models leads to multiple changes in the brain, including
activation of neurons as documented by Fos expression,84,85 alteration
of hypothalamic-pituitary-adrenal axis including elevation of corticotropin-releasing
factor (CRF) concentration,86 and change in
neurotransmitter levels,87 such altered brain-gut
interactions may be a part of the systemic response to a trigger of inflammation.
The immune response to bacterial antigens is known to lead to sickness behavior88 including flu-like symptoms of fatigue, anxiety,
depression,89 and impaired cognition.90 Within that framework, the psychological and psychiatric
comorbidity that are so common in IBS91 and
the response of selected symptoms to cognitive-behavioral therapy or antidepressants92 may be understood.

Conclusions

Given the marked variability of symptoms and findings in patients with
IBS, multiple models of pathophysiology and varying treatment strategies have
been proposed. In this review, the available observations on IBS were considered
and synthesized in an attempt to achieve a goal of integration. In this effort,
it is biologically plausible that the gastrointestinal and extraintestinal
symptoms and findings of IBS have a single, unifying explanation. Specifically,
SIBO provides a framework for understanding IBS by accounting for the following
observations in IBS patients. Nearly all of the symptoms and findings of IBS
are wholly consistent with SIBO, including postprandial bloating (which is
nearly universal), physical evidence of small bowel gas irrespective of predominant
symptoms, high prevalence of abnormal lactulose breath test results, dramatic
reduction in symptoms when antibiotic therapy is given and breath tests subsequently
normalize, altered gut motility, visceral hypersensitivity, abnormal brain-gut
interactions, evidence of autonomic dysfunction, nearly uniform immune activation
regardless of prior acute gastroenteritis, and extraintestinal symptoms that
are often flu-like in quality.

As a unifying framework for understanding IBS and other functional disorders,
SIBO provides a target for exciting research that may lead to better diagnostic
and treatment approaches. SIBO is a condition characterized by a chronic relapsing
clinical course.76 Since indefinite use of
antibiotics is not an attractive option, future research should be directed
at understanding and controlling the interaction between host and gut bacteria.

Bulbring E, Lin RC. The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan
on peristalsis: the local production of 5-HT and its release in relation to
intraluminal pressure and propulsive activity. J Physiol (Lond).1958;140:381-407.PubMedGoogle Scholar